Impact of Azithromycin on ARES in Children with HIV and Chronic Lung Disease

Table of Content

Introduction

Chronic lung disease (CLD) is one of the most common comorbidities among older children and adolescents with HIV. The BREATHE (Bronchopulmonary function in response to azithromycin treatment for chronic lung disease in HIV-infected children) trial investigated whether adjuvant treatment with weekly azithromycin (AZM) for 48 weeks results in improved lung function in children and adolescents aged 6-19 years with HIV taking antiretroviral treatment (ART) who had CLD.

Aim

The aim of post hoc analysis of BREATHE trial was to identify risk factors associated with AREs and mediators of the effect of azithromycin on acute respiratory exacerbations (AREs)

Patient Profile

  • Patients aged 6-19 years
  • Had been on any combination of ART for at least six months and had CLD

Method

  • Multicenter, individually randomised, placebo-controlled trial
  • Post hoc analysis of the BREATHE trial
  • 345 participants
    • 171 allocated to azithromycin
    • 174 allocated to placebo
  •  Risk factors for AREs were examined among participants in both the azithromycin and placebo groups
  • The primary outcome of this analysis was the rate of AREs by study arm up to 49 weeks

Result

  • There were 38 episodes of AREs amongst placebo group participants and 19 total episodes of AREs in the azithromycin arm, over a total of 154 and 157 person years respectively
  • Risk factors for AREs included presence of an abnormal respiratory rate at baseline and having a baseline CD4 count <200/mm3
    • Rates of AREs were higher among those with an abnormally high respiratory rate at baseline (adjusted rate ratio (aRR) 2.08; p-value 0.02) and among those with a CD4 cell count <200 cells/mm3 (aRR 2.71; p-value 0.008)
Table 1: Risk factors for AREs

 

Variable categories

Total episodes of AREs/100 person-years

Model 1 RR1

p-value2

Model 2 RR3

p-value2

Total

 

57/309

 

 

 

 

Age (years)

6-15

30/182

1

0.90

1

0.25

 

16+

27/127

0.96

 

0.69

 

Sex

Male

25/161

1

0.25

1

0.47

 

Female

32/148

1.41

 

1.29

 

Site

Zimbabwe

50/216

1

0.005

1

0.003

 

Malawi

7/93

0.33

 

0.31

 

FEV1 Z-score

≥ 2

21/168

1

0.03

1

0.06

 

<-2

36/141

2.18

 

1.79

 

CD4 count3(cells/mm)

> 200

43/279

1

0.006

1

0.008

 

<200

14/30

3.00

 

2.71

 

HIV VL (copies/ml)

<1000

25/176

1

0.09

1

0.50

 

>1000

32/133

1.67

 

1.30

 

ART line

1st

35/233

1

0.16

1

0.46

 

2nd

22/76

1.59

 

0.90

 

Weight for age Z-score

Not underweight

29/144

1

0.82

1

0.91

 

Underweight

28/165

1.08

 

0.97

 

Height for age Z-score

Not stunted

26/157

1

0.70

1

0.99

 

Stunted

31/152

0.89

 

1.00

 

Presence of a cough

No

45/282

1

0.04

1

0.58

 

Yes

12/27

2.36

 

 

Abnormal RR

No

21/174

1

0.02

1

0.02

 

Yes

36/135

2.19

 

2.08

 

History of TB

No

36/219

1

0.68

1

0.92

 

Yes

21/89

1.15

 

0.97

 

Season

Rainy

21/156

1

0.06

1

0.12

 

Dry

36/153

1.67

 

1.67

 

Calendar Period (years)

2016-2017

35/121

1

0.004

1

0.05

 

2018-2019

22/188

0.44

 

0.49

 

1adjusted for trial arm, age, sex, site, season, calendar time, and HIV VL (continuous)

2p-value from LRT

3adjusted for trial arm, age, sex, site and season, calendar time, HIV VL (continuous), abnormal RR, cough, CD4 count and FEV1 Z-score.

  • The effect of azithromycin by sex (p-value for interaction=0.07); males had a greater reduction in the rate of ARE with azithromycin treatment than females
    •  Azithromycin appeared to reduce AREs by 77% in males but only 23% in females (stratum specific RR in the azithromycin group was 0.23 and 0.77 respectively)
  • Azithromycin had a greater impact on reducing AREs in participants with chronic respiratory symptoms at baseline, those on 1st line ART, with a FEV1 score >-2 and participants without baseline resistance to azithromycin

Conclusion

  • The study identified, baseline abnormally high respiratory rate and CD4 count <200 cells/mm3 were associated with a higher risk of AREs
  • Azithromycin was more effective at reducing AREs in male participants and in participants with chronic respiratory symptoms, an FEV1 Z-score > -2, those on 1st line ART, and without resistance to azithromycin at baseline
  • The findings highlight the use of targeted treatment may reduce concerns regarding the emergence of AMR, and children and adolescents with HIV-associated CLD should be screened for these respiratory symptoms and clinical characteristics to help identify those most at risk of AREs and to guide management

Reference

EClinicalMedicine.2021;42:101195